The goal of this study was to determine whether chronic endogenous sympathetic stimulation resulting from the overexpression of cardiac stimulatory G protein subunit (Gs) in transgenic mice (15.3 q 0.1 mo old) resulted in a clinical picture of cardiomyopathy. The left ventricular ejection fraction, measured by echocardiography, was reduced in older mice with Gs overexpression (50.4 q 5.4%) compared with age-matched control mice (70.9 q 1.6%; P < 0.05). When ejection fractions were compared at similar heart rates, the Gs mice exhibited a greater left ventricular end-diastolic dimension than control mice (4.3 q 0.2 vs. 3.7 q 0.1 mm; P < 0.05). Baseline heart rates were elevated in conscious Gs mice (722 q 27 beats/min; n = 5) compared with control mice (656 q 28 beats/min; n = 5). Moreover, electrocardiographic monitoring demonstrated a high incidence of arrhythmias. Increased mortality compared with control mice (31.6 vs. 3.0%; P < 0.01) was also observed. Thus older mice with Gs overexpression exhibit many of the features of dilated cardiomyopathy. This study supports the concept that chronic sympathetic stimulation over an extended period of time,